Risk factors for anxiety disorder are important in determining who ultimately develops the disorder. However, our understanding of risk factors is rudimentary. Identification of the mechanisms of risk factors would be a step forward in understanding the etiology of anxiety disorders. Reduced hippocampal volume, dysfunction of the brain-derived neurotrophin factor (BDNF) system and behavioral inhibition temperament are three anxiety risk factors identified in humans. The risk factor of reduced hippocampal volume is associated with impaired hippocampal-dependent learning, suggesting impaired hippocampal synaptic plasticity in individuals at risk. BDNF is important for synaptic plasticity. Thus, we hypothesize that impaired hippocampal synaptic plasticity may underlie the risk factors of both reduced hippocampal volume and BDNF dysfunction. The Wistar Kyoto (WKY) rat is an inbred strain that is stress sensitive, has a reduced hippocampal volume compared to the outbred Sprague Dawley (SD) rat, has an abnormal BDNF system and expresses a behavioral inhibition. In addition, WKY rats acquire active avoidance to a greater and more persistent degree than SD rats. Abnormal avoidance is a core feature of all anxiety disorders, and the development of abnormal avoidance parallels the trajectory of PTSD (cluster C). Thus, the proposed studies will test whether impaired synaptic plasticity in the hippocampus contributes to the development of abnormal avoidance learning in the presence and absence of behavioral inhibition temperament. Four aims are proposed. Aim 1 will determine whether BDNF-induced synaptic plasticity is impaired in the hippocampus of WKY rats and if NMDA and BDNF agonists can attenuate these impairments. Aim 2 will investigate the effects of drugs acting on NMDA and BDNF-TrkB receptors on avoidance learning. Aim 3 will determine if opioid-dependent LTP in the hippocampus is impaired in WKY rats. Opioid-dependent LTP does not require NMDA or TrkB receptors. Aim 4 will investigate whether drugs acting on opioid receptors can affect the development of abnormal avoidance responding. Because opioid-dependent LTP is independent of NMDA and TrkB receptors, the comparison of opioid LTP to NMDA- and BDNF-LTP will determine whether the development of abnormal avoidance requires impairment of a specific type of LTP (i.e., NMDA) or if impairment to any of the various forms of LTP in the hippocampus can lead to the development of abnormal avoidance. The proposed studies will start to elucidate the mechanisms and interactions of three risk factors for anxiety disorders. Understanding the etiology of anxiety disorders and mechanisms of risk factors will help in the development of treatments. This is especially important to the health of veterans because a significant number of veterans are likely to develop anxiety-related disorders as a result of the extreme stress associated with combat service.